The ω-diphenylurea derivatives are known compounds with c-RAF kinase inhibition activity. For example, WO2000/042012 disclosed a class of ω-carboxyl-aryl-substituted diphenylurea and the use thereof for treating cancer and related diseases.
Initially, ω-diphenylurea compounds, such as Sorafenib, were firstly found as the inhibitor of c-RAF kinase. The other studies had shown that they could also inhibit the MEK and ERK signal transduction pathways and activities of tyrosine kinases including vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial growth factor receptor-3 (VEGFR-3), and platelet-derived growth factor receptor-β (PDGFR-β) (Curr Pharm Des 2002, 8, 2255-2257). Therefore, they were called multi-kinase inhibitors that resulted in dual anti-tumor effects.
Sorafenib (trade name Nexavar), a novel oral multi-kinase inhibitor, was developed by Bayer and Onyx. In December 2005, based on its outstanding performance in phase III clinical trials for treating advanced renal cell carcinoma, Sorafenib was approved by FDA for treating advanced renal cell carcinoma. It was marketed in China in November 2006. However, Sorafenib has various side-effects, such as hypertension, weight loss, rash and so on.
BAY 73-4506 is a 3-fluoro derivative of Sorafenib, and is also a multi-kinase inhibitor targeting tumors and the vessel thereof. In particular, BAY 73-4506 is an effective inhibitor of Raf kinases, p38 kinase, platelet-derived growth factor receptor (PDGFR) kinase and vascular endothelial growth factor receptor (VEGFR) kinase 2 and 3. Inhibition of these special kinases is closely related to the prevention or treatment of osteoporosis, inflammatory diseases, hyperplastic diseases, angiogenic diseases and cancer (Dumas et al., PCT publication WO 2005009961 A2; Hedbom S et al., Journal of Clinical Oncology, 25, (Suppl. 18): Abs, 3593). At present, this compound is in the phase of clinical evaluation for treating renal cell carcinoma (ClinicalTrials. gov Web Site 2008, May 5), solid tumor (J Clin Oncol, 2008, 26(15, Suppl.): Abst 2558), liver cancer (ClinicalTrials. gov Web Site 2010, May 17) and metastatic colon cancer (ClinicalTrials. gov Web Site 2010, May 17). BAY 73-4506 is in the phase of preclinical evaluation for treating multiple myeloma (Blood, 2008, 112(11): Abst 2766).
However, development of compounds with inhibition efficacy to Raf kinases or better pharmacodynamic properties, and the preparation processes thereof are still in need.